Renal toxicity has been reported with bisphosphonates such as pamidronate and zolidronate but not with ibandronate, in the treatment of breast cancer patients with bone metastasis. One of the patterns of bisphosphonate-induced nephrotoxicity is focal segmental glomerulosclerosis (FSGS) or its morphological variant, collapsing focal segmental glomerulosclerosis (CFSGS).
Trang 1C A S E R E P O R T Open Access
Collapsing focal segmental glomerulosclerosis
following long-term treatment with oral
ibandronate: case report and review of literature
Ning Jia1*, Fionnuala C Cormack2, Bin Xie3, Zita Shiue4, Behzad Najafian5and Julie R Gralow3
Abstract
Background: Renal toxicity has been reported with bisphosphonates such as pamidronate and zolidronate but not with ibandronate, in the treatment of breast cancer patients with bone metastasis One of the patterns of
bisphosphonate-induced nephrotoxicity is focal segmental glomerulosclerosis (FSGS) or its morphological variant, collapsing focal segmental glomerulosclerosis (CFSGS)
Case presentation: We describe a breast cancer patient who developed heavy proteinuria (protein/creatinine ratio 9.1) and nephrotic syndrome following treatment with oral ibandronate for 29 months CFSGS was proven by biopsy There was no improvement 1 month after ibandronate was discontinued Prednisone and tacrolimus were started and she experienced a decreased in proteinuria
Conclusion: In patient who develops ibandronate-associated CFSGS, proteinuria appears to be at least partially reversible with the treatment of prednisone and/or tacrolimus if the syndrome is recognized early and ibandronate
is stopped
Keywords: Collapsing glomerulopathy, Focal segmental glomerulosclerosis, Bisphosphonates, Ibandronate
Background
Bisphosphonates are widely used in the treatment of
pa-tients with metastatic bone diseases They play an
im-portant role in decreasing bone morbidity, preventing
bone complications and managing bone pain
Further-more, emerging evidence suggests that bisphosphonates
may potentially inhibit angiogenesis and tumor cell
inva-sion, induce apoptosis in tumor cells and have
immuno-modulatory effects [1, 2] They have been increasingly
studied in the adjuvant setting of breast cancer
treat-ment and have showed some promising effects [3–5]
Bisphosphonates can be administered either orally or
intravenously Oral ibandronate was evaluated in the
German Intergroup Node-Positive (GAIN) study, in
which patients receiving one of two dose-dense
chemo-therapy regimens were randomized to 2 years of oral
ibandronate versus placebo [6] The first interim efficacy
analysis was also presented at San Antonio Breast Cancer Symposium in December 2011 There was no difference in 3 year disease free survival or overall sur-vival The Southwest Oncology Group (SWOG) S0307 trial is a comparison of three different bisphospho-nates in the adjuvant breast cancer setting This trial randomized 6,000 women with stage I- III breast can-cer receiving standard adjuvant therapy to oral clodro-nate (1600 mg, daily) versus oral ibandroclodro-nate (50 mg, daily) versus zoledronate (4 mg intravenously, monthly for 6 months, then every 3 months), all for 3 years duration This trial recently closed to accrual and will provide further data on the utility of bisphosphonates
in the adjuvant setting
Drug-related side effects are limiting factors to the use
of bisphosphonates Bisphosphonates have been associ-ated with deterioration of renal function and histopatho-logical changes in the kidney Available data suggest that pamidronate and zolidronate, but not ibandronate, are associated with nephrotoxicity in the treatment of pa-tients with malignant disease [7] One of the patterns of nephrotoxicity with bisphophonates is the development
* Correspondence: jianing1976@yahoo.com
1 Department of Medical Oncology, Peking Union Medical College Hospital,
Peking Union Medical College and Chinese Academy of Medical Sciences,
Beijing 100730, China
Full list of author information is available at the end of the article
© 2015 Jia et al This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited The Creative Commons Public Domain Dedication waiver (http://
Trang 2of the focal segmental glomerulosclerosis (FSGS) or its
morphological variant the collapsing focal segmental
glomerulosclerosis (CFSGS), which typically presents
with nephrotic syndrome and renal insufficiency [7] To
our knowledge, no patients with CFSGS and nephrotic
syndrome associated with ibandronate have been
de-scribed in the literature before
Case presentation
A 44-year-old Caucasian female with a family history of
breast cancer and multiple myeloma was seen in clinic
for right breast, stage I, triple negative invasive ductal
carcinoma She had undergone a lumpectomy followed
by adjuvant dose-dense Adriamycin, Cyclophosphamide
(AC) and paclitaxel chemotherapy and radiation She
was enrolled in the SWOG S0370 study and randomized
to the oral ibandronate arm and had been taking oral
ibandronate 50 mg once daily since December 2008 with
stop date scheduled for December 2011 In May 2011,
she presented with new onset lower extremity edema
Laboratory tests at the time revealed heavy proteinuria
with a protein/creatinine ratio 9.1 (g/g), hypoalbuminaemia
(2.1 g/l) and hypercholesterolaemia (14 mmol/l) with no
hematuria and normal serum creatinine (0.7 mg/dl) which
had been consistently normal before She had no
hyperten-sion history A diagnosis of nephrotic syndrome was made
Serological evaluation for HIV, hepatitis C, hepatitis B
virus, antibodies to nuclear antigens (ANA), rheumatoid
factor, anti-neutrophil cytoplasmic antibody (anti-PR3
and anti-MPO), anti cardiolipin, and anti beta 2
glyco-protein 1 were negative Values of serum complement
(total, C3 and C4), free light chain (kappa and lambda),
protein electrophoresis, immnofixation,beta 2
micro-globulin and immunomicro-globulin (A, G and M) were within
normal range There were no spikes by urine and serum protein electrophoresis
A renal biopsy was performed and specimens were sent for light, immunofluorescent and electron micros-copy The biopsy consisted of portions of cortex and me-dulla, containing 10 to 15 glomeruli per level section None of the glomeruli were globally sclerosed About 13–40 % of glomeruli per level section showed segmen-tal obliteration of capillary loops with accumulation of extracellular matrix, hyaline or foam cells in the sclerotic regions and adhesion to Bowman’s capsule, consistent with focal and segmental glomerulosclerosis (FSGS) (Fig 1a) Up to two glomeruli with FSGS showed seg-mental collapse of capillary tufts with proliferation of overlying epithelial cells, characteristic of collapsing glo-merulopathy (Fig 1b) No additional lesion was found in the glomeruli The rest of renal parenchyma showed mild interstitial fibrosis and tubular atrophy, mild and scattered predominantly mononuclear interstitial, in-flammatory infiltrate, diffuse, mild interstitial edema and occasional tubulitis Arterioles were unremarkable, but interlobular arteries showed moderate intimal fibrosis Immunofluorescence studies were unremarkable with no significant glomerular staining for IgG, IgA, IgM, C3, C1q, fibrinogen, kappa or lambda light chains or albu-min Electron microscopy showed extensive effacement
of foot processes involving about 60 to 70 % of capillary surface area (Fig 1c) No electron dense deposit was identified After the diagnosis of nephrotic syndrome, ibandronate was discontinued She initially underwent treatment with lisinopril, simvastatin and furosemide However, after one month, she had no improvement of protenuria Prednisone was started at 60 mg daily About one month later, urine protein/creatinine ratio was re-duced to 4.9 g/g, thus indicative of some improvement
Fig 1 a A glomerulus with FSGS The red arrow marks the segmentally sclerosed region with obliteration of capillary tuft, hyaline deposition and adhesion to Bowman ’s capsule Jones methenamine silver, 40x objective b A glomerulus with collapsing variant of FSGS There is almost diffuse collapse of capillary loops with proliferation of overlying epithelial cells (yellow arrow) Jones methenamine silver, 40x objective c An electron micrograph shows extensive effacement of foot processes (black arrows) over a capillary loop (cap) with corrugated glomerular basement membrane.
4800 X magnification
Trang 3but still within the nephrotic range Therefore, a
calcine-urin inhibitor, tacrolimus 1 mg twice daily was started in
August 2011 and continued through October 2013
Prednisone was tapered off after 7 months in March
2012 Creatinine was relatively stable throughout
treat-ment and Estimated Glomerular Filtration Rate (eGFR)
calculated by Modification of Diet in Renal Disease
(MDRD) equation was normal She is currently on
lisi-nopril 40 mg daily with mild proteinuria
(protein/cre-atinine ratio of 0.5) at the time of this report
Discussion
We report a rare case of collapsing FSGS and nephrotic
syndrome associated with the administration of oral
ibandronate Ibandronate is a single nitrogen-containing
bisphosphonate with higher comparative protein binding
and shorter comparative renal tissue half life than other
bisphosphonates It is Food and Drug Administration
approved for treatment of post-menopausal osteoporosis
(PMO) Outside the United States, ibandronate is
ap-proved by the European Union for the treatment of
PMO and malignancy-associated bone disease
Ibandronate appears to have a safer renal profile with
no evidence of nephrotoxicity Intravenous ibandronate
given over 15 min, 60 min or 15–30 s did not have renal
toxicity, even in patients with preexisting hypertension
or diabetes, although follow up is short [8–10] Fourteen
patients who received a median of 16 monthly infusions
of ibandronate have no renal toxicity [11] With 44
patients and 524 cycles of oral idandronate with a
me-dian of 12 monthly cycles, there is no deterioration of
renal function [12] In patients with preexisting renal
impairment, there is no acute nephrotoxicity with
iban-dronate [13] Results from clinical trials indicate that the
renal safety profile of intravenous and oral ibandronate
is similar to that of placebo for up to 4 years treatment
in metastatic breast cancer [14, 15]
The renal biopsy findings in our patient displayed
FSGS with collapsing features and extensive foot process
effacement, consistent with significant podocyte injury
Pamidronate toxicity targets podocytes, while some
cases of pamidronate-associated toxic acute tubular
necrosis (ATN) have been reported [16] Zoledronate
ap-pears to mainly target tubular epithelium, resulting in a
pattern of toxic ATN, but zoledronate-associated
col-lapsing FSGS has also been reported [17] Therefore,
renal injury of intravenous bisphosphonates is likely to
be very complex and overlap between different agents
We did not identify significant acute tubular injury in
the current biopsy
The renal tolerability of oral bisphosphonates is
rela-tively good However, nephrotoxicity has been reported
with oral bisphosphonates Miura et al reported a single
case of massive proteinuria and acute renal failure after
alendronate administration in a patient with focal seg-mental glomerulosclerosis [18] Stratton et al reported two cases of relapse of steroid-dependent nephrotic syn-drome triggered by etidronate [19] Proteinuria is thus a known feature of bisphosphonate-associated nephrotox-icity In many cases, nephrotic syndrome associated with bisphosphonate is partially or completely reversible fol-lowing discontinuation of bisphosphonate [18–20] The frequency of proteinuria in breast cancer patients with metastatic bone disease receiving intravenous iban-dronate was similar to those receiving placebo or no clinical relevant changes from baseline in 2 randomized trials [10, 21] However the numbers of patients were limited and the study periods were only 3 and 6 months respectively Transient proteinuria after the treatment of intravenous ibandronate for metastatic breast cancer has been reported before [22]
The American Society of Clinical Oncology 2011 Clinical Practice Guideline Update committee recommends that serum creatinine should be monitored before each dose
of pamidronate or zoledronic acid per FDA-approved labeling [23] Serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin should also be monitored regularly Therefore, since proteinuria was not monitored commonly in the patients treated with long-term intravenous and oral ibandronate before, the renal toxicity of ibandronate could be underestimated The etiology for the difference in nephrotoxic poten-tial is not entirely clear, but could relate to pharmacoki-netic differences Ibandronate is more highly protein bound, which may limit renal exposure of free drug The renal tissue half-life of ibandronate is much shorter than zoledronate [24]
Conclusion
We report an unusual case of oral ibandronate-associated CFSGS and nephrotic syndrome Proteinuria appears to be partially reversible with the treatment of prednisone and/or tacrolimus if the syndrome is recognized early and ibandro-nate is stopped We did not have a follow up biopsy to con-firm if the observed improvement in proteinuria was associated with histological amelioration of FSGS or foot process effacement We recommend monitoring protein-uria for earlier detection of worsening renal function in pa-tients with long-term treatment of oral ibandronate Renal biopsy is a key procedure for diagnosis and treatment
Consent Written informed consent was obtained from the patient for publication of this case report and any accompanying images A copy of the written consent is available for review by the editor of this journal
Trang 4FSGS: Focal segmental glomerulosclerosis; CFSGS: Collapsing focal segmental
glomerulosclerosis; GAIN: The German Intergroup Node-Positive; SWOG: The
Southwest Oncology Group; AC: Adriamycin and Cyclophosphamide;
ANA: Antibodies to nuclear antigens; PMO: Post-menopausal osteoporosis;
ATN: Acute tubular necrosis; eGFR: estimated glomerular filtration rate;
MDRD: Modification of diet in renal disease.
Competing interests
The authors declare that they have no competing interests.
Authors ’ contributions
NJ, BX, FC, ZS and JG were involved in the clinical management of the
patient BN contributed pathology review NJ and BX wrote the main
structure of the manuscript FC, ZS, JG, and BN revised the manuscript All
authors read and approved the final manuscript.
Acknowledgements
The authors thank all our colleagues who helped us with outcome data
collection.
Author details
1 Department of Medical Oncology, Peking Union Medical College Hospital,
Peking Union Medical College and Chinese Academy of Medical Sciences,
Beijing 100730, China 2 Division of Nephrology, Harborview Medical Center,
University of Washington, Seattle, WA 98195, USA 3 Division of Oncology,
Department of Medicine, Seattle Cancer Care Alliance, University of
Washington, Seattle, WA 98109, USA 4 Department of Medicine, University of
Washington, Seattle, WA 98195, USA 5 Department of Pathology, University
of Washington, Seattle, WA 98195, USA.
Received: 25 November 2014 Accepted: 9 July 2015
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